Biosynthesis of estrogens occurs when androgens are oxidized with an enzyme called aromatase, formic acid is eliminated, and the androgens are aromatized. Therefore, if it is possible to inhibit the action of aromatase effectively, it is considered to be useful for treatment of diseases caused by excess of estrogens, and, based thereon, it is already revealed that several aromatase inhibitors are useful for treatment of breast cancer and prostatic hypertrophy.
Further, aromatase inhibitors are also useful for treatment of other diseases caused by excess of estrogens, for example, uterine cancer, ovarian cancer, endometriosis, gynecomastia, male infertility based on oligospermia, etc.
As steroidal aromatase inhibitors, there have, for example, been known testolactone (The Merck Index, 10th edition, 8999), 4-hydroxy-4-androstene-3,17-dione and its esters (U.S. Pat. No. 4,235,893), 1-alkylandrosta-1,4-diene-3,17-dione (Japanese Laid-Open Patent Publication No. 13796/1985), 4-substituted androstene-3,17-dione derivatives (Japanese Laid-Open Patent Publication No. 189295/1986), 6-methyleneandrosta-1,4-diene-3,17-dione derivatives (Japanese Laid-Open Patent Publication No. 12797/1987), 16-oxaandrosta-1,4-diene-3,17-dione (J. Med. Chem., 32, 651, (1989)), etc.
On the other hand, as compounds having chemical structure comparatively analogous to that of the compounds of this invention, there have been known 16-azaandrost-4-ene-3,17-dione and 16-methyl-16-azaandrost-4-en-3-one (J. Med. Chem., 10, 177, (1967)), 17-aza-D-homoandrosta-4,6-diene-3,17a-dione (U.S. Pat. No. 3,642,800), 17a-aza-D-homoandrost-4-en-3-one (J. Am. Chem., Soc., 78, 639, (1956)), 17-oxaandrostan-3-one (J. Org. Chem. 49, 3753 (1984)), etc. but there has never been known the use of these compounds as an aromatase inhibitor.
However, known aromatase inhibitors tend to be inactivated by metabolism when administered in living bodies and are not satisfactory for clinical uses.
The present inventors found that a steroidal aromatase inhibitor hard to inactivate by metabolism can be obtained by introducing a hetero atom into the D ring of asteroid.